We have already demonstrated the effectiveness of behavioral interventions (reinforcement for cocaine-negative urine samples) in large inner-city samples of intravenous polydrug abusers, and we continue to evaluate the best ways to apply the treatment. To test whether a combination of contingency management and methadone dose increase would promote abstinence from heroin and cocaine, we conducted a randomized controlled trial using a 2 X 3 (Dose X Contingency) factorial design, in which dose assignment was double-blind, in a consecutive sample of 252 heroin- and cocaine-abusing outpatients on methadone maintenance. A novel contingency was used that reinforced abstinence from either drug while doubly reinforcing simultaneous abstinence from both. The total value of incentives was split between drugs to contain costs. Participants were randomly assigned to methadone dose (70 or 100 mg/day, double blind) and voucher condition (contingent on cocaine-negative urines;split;or noncontingent). The primary outcome measure, percentage of urine specimens negative for heroin, cocaine, and both simultaneously, was monitored for 5 weeks before and 10 weeks after the 12-week interventions. Urine-screen results showed that the methadone dose increase reduced heroin use but not cocaine use. The Split 100mg group was the only group to achieve a longer duration of simultaneous negatives than its same-dose Noncontingent control group. The frequency of DSM-IV opiate and cocaine dependence diagnoses decreased and quality of life measures improved in the active intervention groups. We concluded that methadone does not directly decrease cocaine use (despite recent reports to the contrary) and that, for a split contingency to promote simultaneous abstinence from cocaine and heroin, a relatively high dose of methadone appears necessary but not sufficient;an increase in overall incentive amount may also be required. To follow up on this research on voucher-based contingency management (CM), we investigated the most effective approach to treating heroin/cocaine dependence with prize-based CM. We compared two CM schedules that reinforced either cocaine abstinence only or cocaine plus opiate abstinence, in outpatients maintained on methadone. Drug use was monitored via observed urine specimens collected Mon-Wed-Fri during 5 weeks pre-CM (Baseline), 12 weeks contingency-management intervention (CM intervention), and 8 weeks post-intervention (Maintenance). Participants were randomly assigned to a Cocaine-contingency group (4 prize draws for each cocaine-negative urine) or an Opiate/cocaine-contingency group (1 draw for each urine negative for either opiates or cocaine, or 4 draws if negative for both). Participants drew for prizes chosen from an on-site stock and awarded the same day. Cocaine and opiate abstinence increased from Baseline to Intervention in both groups. There were no significant between-group differences in cocaine abstinence during Intervention or Maintenance and no differences in opiate abstinence during Intervention. Opiate abstinence was significantly greater in the Opiate/cocaine group during Maintenance, and this group reported significantly less heroin craving during Intervention and Maintenance. Number of draws earned per cocaine-negative urine (4 vs. 1) did not differentially affect cocaine use. However, the contingent reinforcement of opiate abstinence enhanced opiate-abstinence outcomes. The major challenge associated with abstinence reinforcement is its likely prohibitive cost and staff/resource intensity, especially when the reinforcement follows an escalating amount schedule. Workflow challenges include varying conditions for meeting inclusion criteria, stratification into various groups, tracking categories of reinforcers chosen, and determination of eligibility for bonus reinforcers based on laboratory results or other protocol-defined criteria. To address these challenges, in collaboration with the Biomedical Informatics Section of the NIDA IRP, we implemented the Automated Contingency Management (ACM) decision support system for abstinence reinforcement. We are continuing to improve the system and to develop mechanisms to make it available to community treatment programs. The availability of such a system would promote technology transfer and increase community use of evidence-based procedures for abstinence reinforcement. In further technology development work, we are exploring the use of handheld electronic devices for treatment delivery in patients daily environment. In individuals who have achieved abstinence, the main concern is the likelihood of relapse. The alpha-agonist lofexidine may help prevent stress-induced relapse to heroin use in patients on methadone maintenance. Both agents, however, exhibit cardiovascular and neurocognitive activities, and the safety of simultaneous administration has never been reported. To determine the electrocardiographic (ECG) effects of co-administration of lofexidine and methadone, we conducted a prospective, double-blind study in fourteen participants with physical dependence on opioids at our outpatient drug treatment research clinic. Participants were stabilized on methadone maintenance therapy (80 mg/day), then received escalating doses of lofexidine for eight weeks. ECGs were performed during peak plasma lofexidine levels. Pre-specified outcome measures were mean and maximal changes in heart rate, PR, QRS, and QTc intervals (1) when stabilized on methadone and (2) after co-administration of lofexidine (0.4 mg). Repeated-measures regression showed no changes in HR, PR, QRS, or QTc after methadone stabilization, but a significant decrease in mean HR after initiating lofexidine. When data were analyzed using maximal ECG response, again, there were no significant changes during methadone induction compared to pretreatment, but there were significant changes in all four ECG parameters when lofexidine was coadministered: decreased HR and increased PR interval, QRS interval, and QTc interval. In three participants, the QTc prolongation was clinically significant (>40 ms). Pending larger studies, our data suggest that coadministration of lofexidine and methadone should be prescribed cautiously, preferably with ECG monitoring.